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Methods to prepare penta-1,4-dien-3-ones and substituted cyclohexanones and derivatives with antitumoral and antiparasitic properties, the compounds and their uses

a technology of penta-1,4-dien-3one and derivatives, which is applied in the field of methods to prepare the 1, 5bis (aryl) penta1, 4dien3one derivatives, which can solve the problems of drug toxicity, parasite resistance, and decrease of patient life quality

Active Publication Date: 2014-10-14
UNIV BANDEIRANTE DE SAO PAULO ACAD PAULISTA ANCHIETA S C +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As observed in the Table below, these drugs present a series of disadvantages, such as relatively high effective doses, low therapeutical index, in addition to undesirable and frequent side effects that undermine patient's condition or that require hospital admission highly decreasing patient's life quality.
In general, both drugs possess good curative index for leishmaniasis for both cutaneous and visceral; however, by the parenteral administration route, parasite resistance and drug toxicity represent the main problems found in the treatment with such drugs (Rev. Soc. Bras. Med. Trop. 33(6), 535-543, 2000).
As shown on the Table above, the several limitations to use the drugs available to treat leishmaniasis are related to their high toxicity that causes several and severe side effects and adverse reactions in a wide spectrum of intensity and severity leading, several times, to treatment discontinuation.
Other factors that difficult or make the use of classic drugs impracticable are: inconvenience of the routes of administration, always parenteral, which discourages patient commitment / or requires an inevitable hospitalization; the refractory nature of some cases to the treatment; drug resistance developed by some species or parasite isolates; and the long term required for the treatment, frequently discontinued by the patient.

Method used

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  • Methods to prepare penta-1,4-dien-3-ones and substituted cyclohexanones and derivatives with antitumoral and antiparasitic properties, the compounds and their uses
  • Methods to prepare penta-1,4-dien-3-ones and substituted cyclohexanones and derivatives with antitumoral and antiparasitic properties, the compounds and their uses
  • Methods to prepare penta-1,4-dien-3-ones and substituted cyclohexanones and derivatives with antitumoral and antiparasitic properties, the compounds and their uses

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of sodium 4-[5-(4-hydroxy-3-methoxy-phenyl)-3-oxo-penta-1,4-dienyl]-2-methoxy-phenolate (codified as DM1)

[0125]

[0126]From 1,5-bis(4-hydroxy-3-methoxy-phenyl)penta-1,4-dien-3-one in the presence of metallic alkoxide in a 1:1 molar ratio. Preferably, 1,5-bis(4-hydroxy-3-methoxy-phenyl)penta-1,4-dien-3-one is mixed with an alcoholic solution of the respective alkoxide, followed by solvent rotoevaporation until solid constitution. Monosalt may be obtained with a high yield. Once obtained, the phenolate is passed through a sieve in order to obtain a fine powder more easily solubilized in water and applied to the biological tests further described in this document.

[0127]The product shows a dark red colour.

[0128]General formula: C19H17O5Na. Molecular weight: 348.

[0129]Yield: 90%.

[0130]Result from Structural Characterization:

[0131]UV-VIS: Maximum absorption 388 nm in water.

[0132]Through acidification with hydrochloric acid, the monosalt is transformed into the correspondent 1,5-...

example 2

Preparation of disodium 3-oxo-penta-1,4-dienyl-bis(2-methoxy-phenolate) codified as DM2)

[0145]

[0146]From the 1,5-bis(4-hydroxy-3-methoxy-phenyl)penta-1,4-dien-3-one in the presence of metallic alkoxide in a 1:2 molar ratio. Preferably, the 1,5-bis(4-hydroxy-3-methoxy-phenyl)penta-1,4-dien-3-one is mixed with an alcoholic solution of the respective alkoxide, followed by a rotoevaporation of the solvent until solid constitution. The disalt can be obtained with high yield. Once prepared, the phenolate is passed though a sieve in order to obtain a fine powder more easily solubilized in water and applied to the biological tests further described in this document.

[0147]The product shows a dark red colour.

[0148]General formula: C19H16O5Na2. Molecular weight: 370.

[0149]Yield: 95%.

[0150]Results from Structural Characterization:

[0151]UV-VIS: Maximum absorption is 370 nm in water.

[0152]Through hydrochloric acid acidification, the correspondent disalt is transformed into the correspondent 1,5-b...

example 3

Preparation of the 3,5-Bis-[3-methoxy-4-(3-methyl-but-2-enyloxy)-phenyl]-4-nitro-cyclohexanone (codified as C-25)

[0153]

Procedure for Preparation A

[0154]Previously, prepare a mixture containing from 5 to 20 mL of dimethylformamide, 1.38 g (0.01 mol) anhydrous potassium carbonate, and 0.01 mol (0.54 mL) of nitromethane, which should be heated under reflux at 20 to 70° C., stirring up for 30 to 60 minutes. After this period of time, add 0.001 mol (540 mg) of the compound 1,5-Bis[3-methoxy-4-(3-methyl-but-2-enyloxy)-phenyl]penta-1,4-dien-3-one dissolved in an appropriated quantity of dimethylformamide and let it heat under stirring for a period of 5 to 15 hours. After this time, the mixture are dropped into water and ice, acidified, extracted with ethyl acetate as required, and the organic phase washed with destined water. Dry with anhydrous sodium sulfate and rotoevaporate the solvent, obtaining the product of reaction.

Procedure for Preparation B

[0155]In this preparation procedure, an ...

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Abstract

The present invention refers to new derivatives of the penta-1,4-dien-3-ones, as well as their processes of preparation. These compounds present strong antitumoral activity and promising antiparasitic action, behaving as almost atoxic by laboratory assays and also by hystopathologic studies. The present invention refers also to a pharmaceutical composition including the referred compounds, method of treatment for cancer and parasitic diseases.

Description

CROSS REFERENCE TO RELATED APPLICATION(S)[0001]This application is a 35 U.S.C. §371 National Phase Entry Application from PCT / BR2007 / 000175, filed Jul. 6, 2007, and designating the United States. This application also claims the benefit of Brazilian Application No. PI-0602640-0, filed Jul. 6, 2006, the disclosure of which is incorporated herein in its entirety by reference.FIELD OF THE INVENTION[0002]The present invention refers to methods to prepare the 1,5-bis(aryl)penta-1,4-dien-3-one derivatives, covering from its synthetic methods of preparation and purification up to their in vivo biological applications as antitumoral agents and in vitro applications as antiparasite agents, among others.[0003]The present invention refers also to a chemical composition that presents pharmaceutical applicability, which includes the referred compounds, to treat cancer and parasitosis.DESCRIPTION OF THE PRIOR ART[0004]H. van der Goot et al. (Eur. J. Med. Chem. 32, 625-630, 1997) have obtained 1,5...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/12C07C45/00
CPCC07C255/37C07C45/64C07C49/255C07C51/367C07C59/90C07C67/14C07C69/78C07C201/12C07C205/37C07C205/45C07C253/30C07C2101/14C07C2601/14A61P33/00A61P33/02A61P35/00C07C255/46
Inventor SUAREZ, JOSE AGUSTIN QUINCOCESMARIA, DURVANEI AUGUSTORANDO, DANIELA GONCALESMARTINS, CLIZETE APARECIDA SBRAVATEPARDI, PAULO CELSODE SOUZA, PAMELA OLIVEIRA
Owner UNIV BANDEIRANTE DE SAO PAULO ACAD PAULISTA ANCHIETA S C
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